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I PROPOXYPHENE, NORPROPOXYPHENE, AND

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I PROPOXYPHENE, NORPROPOXYPHENE, AND PROPOXYPHENE, NORPROPOXYPHENE, AND PROADIFEN (SKF-525A) ARE MECHANISM-BASED INHIBITORS OF CYP3A4, CYP3A5, AND CYP3A IN HUMAN LIVER MICROSOMES Anna Ruth Riley Submitted to the faculty of the University Graduate School in partial fulfillment of the requirements for the degree Master of Science in the Department of Pharmacology and Toxicology, Indiana University December 2008 i Accepted by the Faculty of Indiana University, in partial fulfillment of the requirements for the degree of Master of Science. ___________________________ Sherry F. Queener, Ph.D., Chair ___________________________ David R. Jones, Ph.D. Master’s Thesis Committee ___________________________ David A. Flockhart, M.D., Ph.D. ___________________________ Lynn R. Willis, Ph.D. ii DEDICATION Special thanks to my family, and friends (especially MK), and MJK who helped me during this journey iii ACKNOWLEDGEMENTS To my committee: Sherry F. Queener David R. Jones David A. Flockhart Lynn R. Willis Eli Lilly and Company, for sponsorship iv ABSTRACT Anna Ruth Riley PROPOXYPHENE, NORPROPOXYPHENE, AND PROADIFEN (SKF-525A) ARE MECHANISM-BASED INHIBITORS OF CYP3A4, CYP3A5, AND CYP3A IN HUMAN LIVER MICROSOMES The purpose of this study is to determine if propoxyphene and norpropoxyphene are mechanism-based (irreversible) inhibitors of CYP3A, and to determine if propoxyphene and norpropoxyphene are reversible inhibitors of CYP3A. Mechanism- based inhibition is a type of irreversible inhibition that results from an inhibitor or its metabolite binding to an enzyme during drug metabolism, which renders the enzyme nonfunctional. Propoxyphene is an analgesic that is frequently prescribed in the United States and Europe. It is metabolized by CYP3A enzymes, and is an irreversible inhibitor of CYP3A4. The major metabolite of propoxyphene is norpropoxyphene, which has not been extensively studied for enzyme inhibition. Proadifen (SKF-525a) is not a marketed drug, but it is a known CYP inhibitor that is structurally similar to propoxyphene and norpropoxyphene. Propoxyphene, norpropoxyphene, and proadifen were characterized in these studies with CYP3A4(+b5), CYP3A5(+b5) and pooled human liver microsomes. Time-dependent and concentration-dependent loss of activity of CYP3A was measured by formation of testosterone product. Propoxyphene and norpropoxyphene exhibited the greatest inhibition with CYP3A in human liver microsomes, followed by CYP3A4(+b5), and CYP3A5(+b5). Both compounds formed metabolic-inhibitor complexes with v CYP3A4(+b5) and CYP3A5(+b5), but not with human liver microsomes. Proadifen was a more potent inhibitor of CYP3A4(+b5) than of human liver microsomes and CYP3A5(+b5). The KI values of propoxyphene and CYP3A4(+b5) and human liver microsomes fall within the range of reported therapeutic blood levels of propoxyphene, with reversible inhibition constants (Ki values) above therapeutic blood concentrations for propoxyphene and norpropoxyphene. The KI values of norpropoxyphene and CYP3A4(+b5) and human liver microsomes are higher than most reported blood levels, except for blood levels after repeated dosing of propoxyphene at high concentrations. The predicted change in the area under the plasma concentration versus time curve of an orally administered CYP3A substrate with propoxyphene (AUC'po/AUCpo) was calculated for common CYP3A substrates. The AUC'po/AUCpo ratios are four to twenty-five times higher with co-administration of propoxyphene based on in vitro kinetic parameters. Propoxyphene and norpropoxyphene may cause adverse events when chronically administered at high doses and/or when co-administered with other CYP3A substrates. Sherry F. Queener, Ph.D., Chair vi TABLE OF CONTENTS LIST OF TABLES……………………………………………………………..................ix LIST OF SCHEMATICS………………………………..……………..……....................x LIST OF EQUATIONS………………………………………..……………....................xi LIST OF FIGURES………………………………..……………..……….......................xii ABBREVIATIONS……………………………………………….….……....................xiv CHAPTER 1-INTRODUCTION………………………….…….……….…………….….1 Purpose of the study……………………………….…….…….………...........…...2 Background information on the compounds used in this study..………..….…......3 Background information on enzyme inhibition……….....…...…...…...….............5 Background information on enzymes used in this study.....…...…...…..................7 CHAPTER 2-MATERIALS AND METHODS…….…….…...…...…...……….......…..11 Overview of methods used in the study……….........……......……...……..….....11 Chemicals………………………………………………............….......................11 Enzymes……………………………………………….........……........................11 Mechanism-Based (Irreversible) Inhibition Experiments…….........…......….......12 Reversible Inhibition Experiments………………….…...……............................13 Metabolic-Intermediate Complex Formation Experiments…………......….........14 Data Modeling for Inhibition….…………………………..............….....….........15 Experimental Predictions of In Vivo Drug Interactions with Propoxyphene and Norpropoxyphene……………………………......................................................16 CHAPTER 3-RESULTS………………………………….......…...…........…..................17 Chromatography Data…….……….…….…………………...…..........................17 vii Irreversible Enzyme Inhibition Data………………….………….........................17 Metabolic-Intermediate Complex Formation Data………………….…...............19 Reversible Enzyme Inhibition Data…………..…………….…………...….........20 A Comparison of Irreversible and Reversible Enzyme Inhibition Data................20 CHAPTER 4-DISCUSSION.……….………………..…………...…...….......................22 CHAPTER 5-CONCLUSION……......……………….....…............................................34 APPENDIX-SUMMARY OF STATISTICAL METHODS.............................................76 REFERENCES…………………………………………..................................................77 CURRICULUM VITAE viii LIST OF TABLES Table 1. Chemical Structures of Propoxyphene, Methadone, Codeine, Norpropoxyphene and Dinorpropoxyphene Table 2. Proadifen (SKF-525a) and SKF-8742 Chemical Structures Table 3. List of CYP3A4 and CYP3A5 Common Polymorphisms Table 4. Summary of Kinetic Parameters for Enzyme Inactivation (Irreversible Inhibition) with Propoxyphene, Norpropoxyphene, and Proadifen Table 5. Reversible Inhibition Ki Values Table 6. Reported Therapeutic (Total) Blood Levels of Propoxyphene and Norpropoxyphene Table 7. Predictions of Propoxyphene and Norproxyphene Interactions with Other CYP3A Substrates (AUC'po/AUCpo) ix LIST OF SCHEMATICS Schematic I. Irreversible Inhibition Schematic II. Irreversible Inhibition: Chemistry of Proposed Metabolic-Intermediate Complex Formation Schematic III. Reversible Inhibition x LIST OF EQUATIONS Equation 1. Irreversible Equation for Enzyme Activity (at time (t)), Enzyme Activity at Time (0), and Kobserved (Kobs) at Time (t) Equation 2a and 2b. Irreversible Inhibition Equation for kobserved, kinact, and KI and Enzyme Activity Equation 3. Competitive Inhibition Equation Equation 4. Noncompetitive Inhibition Equation Equation 5. Uncompetitive Inhibition Equation Equation 6. Calculating AUC'po/AUCpo Using Kinetic Parameters xi LIST OF FIGURES Figure 1. HPLC Chromatogram of Extracted Sample After Incubation with Recombinant CYP Figure 2. HPLC Chromatogram of Extracted Sample After Incubation with Human Liver Microsomes Figure 3. Propoxyphene and CYP3A4(+b5)-Percent Activity v. Pre-incubation Time. Figure 4. Propoxyphene and CYP3A5(+b5)-Percent Activity v. Pre-incubation Time Figure 5. Propoxyphene and Human Liver Microsomes-Percent Activity v. Pre- incubation Time Figure 6. Norpropoxyphene and CYP3A4(+b5)-Percent Activity v. Pre-incubation Time Figure 7. Norpropoxyphene and CYP3A5(+b5)-Percent Activity v. Pre-incubation Time Figure 8. Norpropoxyphene and Human Liver Microsomes-Percent Activity v. Pre- incubation Time Figure 9. Proadifen and CYP3A4(+b5)-Percent Activity v. Pre-incubation Time Figure 10. Proadifen and CYP3A5(+b5)-Percent Activity v. Pre-incubation Time Figure 11. Proadifen and Human Liver Microsomes-Percent Activity v. Pre-incubation Time Figure 12. kobs v. Inhibitor Concentration for CYP3A4(+b5) and Propoxyphene Figure 13. Kobs v. Inhibitor Concentration for CYP3A5(+b5) and Propoxyphene Figure 14. Kobs v. Inhibitor Concentration for Human Liver Microsomes and Propoxyphene Figure 15. Kobs v. Inhibitor Concentration for CYP3A4(+b5) and Norpropoxyphene Figure 16. Kobs v. Inhibitor Concentration for CYP3A5(+b5) and Norpropoxyphene xii Figure 17. Kobs v. Inhibitor Concentration for Human Liver Microsomes and Norpropoxyphene Figure 18. Kobs v. Inhibitor Concentration for CYP3A4(+b5) and Proadifen Figure 19. Kobs v. Inhibitor Concentration for CYP3A5(+b5) and Proadifen Figure 20. Kobs v. Inhibitor Concentration for Human Liver Microsomes and Proadifen Figure 21. Propoxyphene and CYP3A4(+b5)-Percent Activity Relative to Control Figure 22. Propoxyphene and CYP3A5(+b5)-Percent Activity Relative to Control Figure 23. Propoxyphene and Human Liver Microsomes-Percent Activity Relative to Control Figure 24. Norpropoxyphene and CYP3A4(+b5)-Percent Activity Relative to Control Figure 25. Norpropoxyphene and CYP3A5(+b5)-Percent Activity Relative to Control Figure 26. Norpropoxyphene and Human Liver Microsomes-Percent Activity Relative to Control Figure 27. Proadifen and CYP3A4(+b5)-Percent Activity Relative to Control Figure 28. Proadifen and CYP3A5(+b5)-Percent Activity Relative to Control Figure 29. Proadifen and Human Liver Microsomes-Percent Activity Relative to Control Figure 30. Metabolic-Intermediate Complex Formation
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